"The U.S. Food and Drug Administration today approved two new drugs, Tafinlar (dabrafenib) and Mekinist (trametinib), for patients with advanced (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin "...
The following adverse reactions are discussed in greater detail in another section of the label.
- New Primary Cutaneous Malignancies [see WARNINGS AND PRECAUTIONS]
- Tumor Promotion in BRAF Wild-Type Melanoma [see WARNINGS AND PRECAUTIONS]
- Serious Febrile Drug Reactions [see WARNINGS AND PRECAUTIONS]
- Hyperglycemia [see WARNINGS AND PRECAUTIONS]
- Uveitis and Iritis [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of TAFINLAR was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily as monotherapy until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg).
Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies]. Trial 1, a multi-center, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m² intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology ( > Grade 2), corrected QT interval ≥ 480 milliseconds on electrocardiogram, or a known history of glucose-6- phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% white, and had a median age of 53 years.
The most commonly occurring adverse reactions ( ≥ 20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).
The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent ( ≥ 2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%).
Table 3: Selected Common Adverse Reactions Occurring
in > 10% (All Grades) or > 2% (Grades 3 or 4) of Patients Treated with
|Primary System Organ Class
N = 187
N = 59
|All Grades (%)||Grades 3 and 4b (%)||All Grades (%)||Grades 3 and 4 (%)|
|Skin and subcutaneous tissue disorders|
|Alopecia||22||NA f||2||NA f|
|Palmar-plantar erythrodysesthesia syndrome||20||2||2||0|
|Nervous system disorders|
|General disorders and administration site conditions|
|Musculoskeletal and connective tissue disorders|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)|
|Respiratory, thoracic, and mediastinal disorders|
|Infections and infestations|
|a Adverse drug reactions, reported using
MedDRA and graded using CTCAE version 4.0 for assessment of toxicity.
b Grade 4 adverse reactions limited to hyperkeratosis (n=1) and constipation (n=1).
c Includes skin papilloma and papilloma.
d Includes squamous cell carcinoma of the skin and keratoacanthoma.
e Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per
Table 4 : Incidence of Laboratory Abnormalities
Increased from Baseline Occurring at a Higher Incidence in Patients Treated
with TAFINLAR in Trial 1 [Between Arm Difference of ≥ 5% (All
Grades) or ≥ 2% (Grades 3 or 4)]
|All Grades (%)||Grades 3 and 4 (%)||All Grades (%)||Grades 3 and 4 (%)|
|Increased Alkaline phosphatase||19||0||14||2|
|a Grade 4 laboratory abnormality limited to hypophosphatemia (n=1).|
Other clinically important adverse reactions observed in < 10% of patients (N = 586) treated with TAFINLAR were:
Gastrointestinal Disorders: Pancreatitis.
Immune System Disorders: Hypersensitivity manifesting as bullous rash.
Read the Tafinlar (dabrafenib capsules) Side Effects Center for a complete guide to possible side effects
Effects of Other Drugs on Dabrafenib
Drugs that Inhibit or Induce Drug-Metabolizing Enzymes
Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease, respectively, concentrations of dabrafenib [see CLINICAL PHARMACOLOGY]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.
Drugs that Affect Gastric pH
Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib. When TAFINLAR is coadministered with a proton pump inhibitor, H2-receptor antagonist, or antacid, systemic exposure of dabrafenib may be decreased and the effect on efficacy of TAFINLAR is unknown.
Effects of Dabrafenib on Other Drugs
Dabrafenib induces CYP3A4 and may induce other enyzmes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters. Dabrafenib decreased the maximum concentration (Cmax) and area under the curve (AUC) of midazolam (a substrate of CYP3A4) by 61% and 74%, respectively [see CLINICAL PHARMACOLOGY]. Coadministration of TAFINLAR with other substrates of these enzymes, including warfarin, dexamethasone, or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use In Specific Populations]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.
Last reviewed on RxList: 6/6/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Tafinlar Information
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